miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb–E2F1 activity through a feedback loop by targeting CDK6 and CDC25A

  1. Xiaojing Yang1,3,
  2. Min Feng1,3,
  3. Xia Jiang1,
  4. Zhenlong Wu1,
  5. Zhimei Li1,
  6. Meiyee Aau1 and
  7. Qiang Yu1,2,4
  1. 1Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology, and Research), Singapore 138672;
  2. 2Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
    1. 3 These authors contributed equally to this work.

    Abstract

    The Rb–E2F pathway drives cell cycle progression and cell proliferation, and the molecular strategies safeguarding its activity are not fully understood. Here we report that E2F1 directly transactivates miR-449a/b. miR-449a/b targets and inhibits oncogenic CDK6 and CDC25A, resulting in pRb dephosphorylation and cell cycle arrest at G1 phase, revealing a negative feedback regulation of the pRb–E2F1 pathway. Moreover, miR-449a/b expression in cancer cells is epigenetically repressed through histone H3 Lys27 trimethylation, and epigenetic drug treatment targeting histone methylation results in strong induction of miR-449a/b. Our study reveals a tumor suppressor function of miR-449a/b through regulating Rb/E2F1 activity, and suggests that escape from this regulation through an aberrant epigenetic event contributes to E2F1 deregulation and unrestricted proliferation in human cancer.

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